The present invention relates to a process for the preparation of morpholine derivatives, and in particular, the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, which are useful as therapeutic agents.
Compounds of formula (I), below, which are described in International patent specification No. WO 95/16679 (published Jun. 22, 1995), are potent and selective substance P (or neurokinin-1) receptor antagonists. 
wherein
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl, and
(4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3; and
Z is C1-4alkyl.
In particular, the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine has shown potential in the treatment of emesis, depression and anxiety. Substance P antagonists are also being investigated for other neuropsychiatric diseases, including bipolar disorder and schizophrenia, as well as postherpetic neuralgia and pain.
International patent specification No. WO 95/16679 describes the preparation of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine (hereinafter referred to as Compound A), which has the structure: 
by a two-step process starting from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine. With reference to Examples 70 and 75 in WO 95/16679, Compound A is prepared as follows: 
This prior art process and in particular its requirement for a high temperature cyclisation step presents a number of practical difficulties which render it inconvenient when attempted on anything other than a relatively small scale. Therefore, there is a need for the development of a process which is readily amenable to scale-up and hence capable of practical application to the manufacturing plant.
The present invention accordingly provides a convenient, efficient process which utilizes a one-step alkylation with 3-chloromethyl-1,2,4-triazolin-5-one at ambient temperature that produces compounds of formula (I), and in particular Compound A, in a higher yield than the prior art two-step synthesis and which avoids a high temperature cyclisation. The novel process of the present invention is not only more energy efficient (since it requires no heating), but it is also more productive allowing for a shorter time-cycle on large scale and a higher operating concentration. The ability to effect the process of the present invention in one reaction vessel, in which the desired product crystallises from the reaction mixture at ambient temperature is a clear advantage over the prior art synthesis.
Thus, in a first aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) 
wherein
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl, and
(4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3; and
Z is C1-4alkyl,
which comprises:
(i) reacting a compound of formula (II) 
xe2x80x83or a salt thereof, wherein R2, R3, R6, R7, R8, R11, R12, R13 and Z are as previously defined, with a compound of formula (III) 
xe2x80x83wherein LG is a leaving group selected from halogen (e.g. bromo, chloro or iodo) or an alkyl- or arylsulfonate group (e.g. mesylate or tosylate), in an organic solvent and in the presence of a base; and
(ii) collecting the resultant crystalline compound of formula (I).
In a particularly preferred aspect of the present invention, there is provided a process for the preparation of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine which comprises:
(i) reacting 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine or a salt thereof, with a compound of formula (III) 
xe2x80x83as previously defined, in an organic solvent and in the presence of a base; and
(ii) collecting the resultant crystalline 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) -4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine.
In the compounds of formulae (I) and (II), preferably R2 and R3 are both independently hydrogen.
In the compounds of formulae (I) and (II), preferably R6 and R7 are independently selected from fluoro and xe2x80x94CF3. In particular. R6 and R7 are both independently xe2x80x94CF3.
In the compounds of formulae (I) and (II), preferably R8 is hydrogen.
In the compounds of formulae (I) and (II), preferably R11 is hydrogen or fluoro.
In the compounds of formulae (I) and (II), preferably R12 and R13 are both independently hydrogen.
In the compounds of formulae (I) and (II), preferably Z is xe2x80x94CH3.
In the compound of formula (III), preferably, the leaving group LG is chloro.
Suitable bases of use in the above reaction include organic bases or, more preferably, inorganic bases. Suitable organic bases include diisopropylethylamine or triethylamine. Suitable inorganic bases include sodium hydride or potassium carbonate.
Suitable organic solvents of use in the above reaction include diimethylformamide (especially where an inorganic base is used) and acetonitrile (especially where an organic base is used).
Most preferably, the above reaction is effected in, dimethylformamide in the presence of potassium carbonate.
Conveniently, the above reaction is effected at room temperature.
Conveniently, the compound of formula (II), and in particular 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine, of use in step (i) of the above reaction is in the form of its free base. Preferably the compound of formula (II), and in particular 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine, of use in step (i) of the above reaction is in the form of its (R)-camphor sulfonic acid salt. More preferably, the compound of formula (II), and in particular 2-(R)-(1R)-(3,5-bis-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine, of use in step (i) of the above reaction is in the form of its para-toluenesulfonic acid salt.
According to a further or alternative aspect of the present invention, there is provided a process for the preparation of 3-chloromethyl-1,2,4-triazolin-5-one which comprises:
(i) treatment of semicarbazide hydrochloride with benyloxyacetyl chloride under Schotten-Baumann conditions to give benzyloxyacetylsemicarbazide;
(ii) cyclisation of the product of step (i) under basic conditions to give 3-benyloxymethyl-1,2,4-triazolin-5-one;
(iii) hydrogenation of the product of step (ii) to give 3-hydroxymethyl-1,2,4-triazolin-5-one; and
(iv) treatment of the product of step (iii) with a chlorinating agent to give 3-chloromethyl-1,2,4-triazolin-5-one.
According to yet a further or alternative aspect of the present invention, there is provided a process for the preparation of 3-hydroxymethyl-1,2,4-triazol-5-one which comprises steps (i) to (iii) as described above.
In step (i) above, the Schotten-Baumann conditions preferably involve use of aqueous alkali in a suitable solvent such as an ether, for example, tetrahydrofuran, at a reduced temperature, for example, between xe2x88x9210xc2x0 C. and +10xc2x0 C., preferably 0xc2x0 C. A particularly suitable aqueous alkali is aqueous sodium hydroxide.
In step (ii) above, cyclisation is preferably effected in the presence of a base such as an alkali metal hydroxide, for example, sodium hydroxide, at an elevated temperature, conveniently at reflux.
In step (iii) above, hydrogenation may be effected by catalytic hydrogenation using hydrogen in a suitable organic solvent such as an alcohol, for example, methanol, in the presence of a noble metal catalyst such as palladium or platinum or an oxide thereof on a support such as charcoal, and conveniently at room temperature and pressure. More preferably, the hydrogenation is effected by transfer hydrogenation in a suitable organic solvent such as an alcohol, for example, methanol, using a hydrogenation catalyst, in particular, palladium on charcoal, in the presence of a hydrogen donor such as sodium hypophosphite, triethylammonium formate, potassium formate, ammonium formate or cyclohexene. Ammonium formate in water is especially preferred. The transfer hydrogenation is preferably effected at an elevated temperature, for example, between 50xc2x0 C. and 70xc2x0 C., and preferably between 55xc2x0 C. and 60xc2x0 C.
In step (iv) above, the chlorinating agent is, for example, an inorganic, acid chloride such as SOCl2, PCl5, PCl3 and POCl3. Thionyl chloride (SOCl2) is particularly preferred. The reaction is preferably effected in an organic solvent such as acetonitrile, conveniently at room temperature and pressure.